Two large scale nonhuman primate (NHP) efficacy studies have convincingly demonstrated that CMV/SIV vectors can 1) re-infect CMV-seropositive rhesus macaques (RM), 2) during re-infection, elicit potent and persistent SIV-specific CD4+ and CD8+ T cell responses with a strong "effector memory bias", and 3) protect ~50% of vaccinated RM from progressive SIV infection after limiting dose rectal challenge with the highly pathogenic, CCR5-tropic SIVmac239 virus. The protection manifested in these RM is distinct from previous vaccines in its abruptness and extent, with protected RM manifesting a viral burst in plasma of varying size upon initial infection, followed by immediate control to undetectable levels. Protection correlates with the extent of total SIV-specific CD8+ T cells generation during the vaccine phase, and is stable in the vast majority of protected RM for at least 6 months. These data indicate a novel pattern of protection consistent with very early control, likely taking place in the site of viral entry and/or early sites of viral replication and amplification, and mediated by tissue-resident CD8+ TEM. Significantly, the epitope targeting of RhCMV-vectored, SIV-specific CD8+ T cell responses is distinct from responses elicited by conventional viral vectors or SIV itself, excluding the typical immunodominant epitopes that are internally processed in and presented by virally infected cells. This differential CD8+ T cell targeting of wildtype (wt) RhCMV vectors is mediated by the activity of RhCMV genes that inhibit class I MHC-restricted Ag presentation (US2-11 homologues), as US2-11 deletant RhCMV vectors elicit CD8+ T cell responses that include prominent responses to the conventional SIV epitopes. In this renewal, we will define the immunobiology of RhCMV-vector mediated protection, including the mechanisms, timing and location of protection and the impact of differential CD8+ T epitope targeting on the efficiency of SIV control, in particular asking the question whether broadening RhCMV/SIV-vectored responses to include typical dominant epitopes can enhance efficacy.